Alkylglycerols are lipids with a glycerol backbone, to which fatty acid derivatives are coupled by means of an ether bond instead of the ester bond that characterizes most mono-di-and triglycerides and related phospholipids. The ether lipids are present in high concentrations in human bone marrow, spleen and liver (Horrocks, 1972). They contain both saturated and mono-unsaturated 16- and 18- carbon fatty acids. Some are methyl/methoxy-substituted at the fatty acid in the 1-position (Boeryd et al.) or in the 2-position. (Hermann et al.)
The naturally occurring alkylglycerols are in most cases esterified with fatty acids of 16-18 C-atoms, sometimes unsaturated. It is of interest to point out the similarity in size and structure between these esters and the triglycerides.
______________________________________ CH.sub.2.OH CH.sub.2.OH CH.OH CH.OH CH.sub.2.OH CH.sub.2.O.R. Glycerol Alkylglycerol CH.sub.2.O.CO.R CH.sub.2.O.CO.R CH.O.CO.R. CH.O.CO.R CH.sub.2.O.CO.R CH.sub.2.O.R Triglyceride Alkylglycerol ester ______________________________________
Sandler was the first to show that treatment with the alkylether batyl alcohol had a hematopoietic effect in rats as well as in human subjects. His results have been confirmed by Arturson and Lindback, who found that mice treated with batyl alcohol showed an increase both in the erythrocyte and in the reticulocyte count.
Brohult and Holmberg (1954) used the unsaponifiable portion of different bone marrow fats as well as preparations containing esters of alkylglycerols in child leukemia. A maturing effect on the white blood cells was observed. This preliminary investigation was followed up by experiments employing alkylglycerols in irradiation leucopenia. (Alexander et al., 1959)
In 1963 Astrid Brohult published a thesis on alkylglycerols and their use in radiation treatment. The alkylethers used were isolated from Greenland shark liver (Somniosus microcephalus) by molecular distillation followed by hydrolysis.
In patients with uterine cancer it was shown that the decrease in white cells and thrombocytes which usually occurs during radiation treatment is less pronounced if alkylglycerols are administered during this treatment.
In experiments on irradiated rats, it was shown that alkylglycerols or their esters inhibit, to a certain extent, the decrease of both megacaryocytes and nucleated cells in the bone marrow in connection with irradiation.
In 1977 it was shown that the incidence of injuries following radiation therapy for carcinoma of the uterine cervix was significantly decreased when the patients were treated with alkylglycerols. (Brohult et al.) In 1979 it was shown that the frequency of severe fistulas (recto-vaginal and vesico-vaginal) was reduced by 47% when alkylglycerols were administered prior to radiation treatment. (Brohult et al.)
The aim of Brohult's early investigations was to study the effect of alkyldiacylglycerols on granulocytopenia after radiation. When the results were analyzed later, it was found that patients given alkyldiacylglycerols had a higher survival rate than the controls. When comparing the groups, standardized proportions of stages were used. The radiation treatment was the same for the two groups. After 3 years, the group treated with alkyldiacylglycerols showed a higher survival rate that the controls, and after 5 years the survival rate was still higher, and the difference was significant (p &lt;0.05). It is interesting to note that the survival rate was higher for all tumor stages in patients treated with ether lipids than in the corresponding control groups.
In a double-blind study performed in 1970-1972, there was a tendency toward lower stages in patients treated with alkylglycerols in comparison to controls, and a study carried out in the years 1973-1975 also showed a shift to lower stages in the prophylactically treated patients. (Brohult et al., 1986)
When all groups of patients with uterine cancer are put together (1964-1966, 1970-1972, 1973-1975) the total amount of patients studied consists of 841 prophylactically treated cases and 4404 control cases (=usual radiation therapy without alkoxyglycerol treatment). The mortality after five years in the prophylactic group was 31.0 percent while the mortality in the corresponding control group was 39.6 per cent. The difference is statistically significant (p&lt;0.001). (Brohult et al., 1986)
In a study by Brohult et al 1972 it was observed that patients vaccinated against typhoid-paratyphoid before implantation of radium for uterine cancer and given alkylglycerols produced antibodies to a larger extent than a control group receiving radiation treatment but not alkoxyglycerols.
In animal experiments it has been shown (Boeryd et al, 1978, 1980) that methoxy-substituted alkylglycerols in the feed stimulates the immune reactivity in mice against red blood cells as determined by the number of plaque-forming cells. Further the methoxy-substituted alkylglycerols stimulated cellular immunoreactivity as demonstrated by the increased ability of parenteral spleen cells to endure a graft-versus-host reaction in hybrid mice.
About 2% of the alkylglycerols in the Greenland shark liver oil consists of methoxy-substituted alkylglycerols with the methoxy group in the 1-position.
Chemotherapy for cancer has essentially remained the same for the last twenty years. There have been several variations of the standard CMF, CMFVP, CMFT, and CAF, but no breakthrough in new modalities or combination treatments that have yet proven effective.
Since no chemotherapy combination has improved survival, it seems reasonable to attempt to modify the milieu that the tumor presided in. Burns and Spector's findings suggested a potential role for lipid nutrition in cancer therapy. It has been well documented that fatty acid content of cancer cell membranes can change substantially when the cells are exposed to different types of fat. Certain physical and functional properties of the membrane are modified making the cells more sensitive to treatment of doxorubicin. The purpose of this study was to evaluate the use of Alkylglycerols in the treatment of cancer by examining its effect on inhibiting cellular growth and augmenting cytotoxic effects of chemotherapeutic agents.
The increasing incidence of cancer may be related to our diet which is high in saturated fats and vegetable oil. Lissner et al. have shown that the type of fat consumed influences the occurrence of endometrial cancer. Shu et al. found in a study in China that diets high in animal fat may play an important role in the ideology of endometrial cancer. A review in the British Medical Journal by Austoker et al concluded that diet is a major factor in the aetiology of cancer of the large bowel and stomach. Zhang et al. concluded that high fat intake is associated with reduced survival in post menopausal women with breast cancer.
Methoxy-substituted alkylglycerols have been shown to inhibit tumor growth in cultured cell lines. (Hallgrasen et al., 1978). Recent studies postulate that these substances can both stimulate the immune system and inhibit tumors.
Alkylglycerols may exert their beneficial effects by modifying membrance structure and function and by altering signal transduction. Membrane fatty acids can be altered by diet in animals. Such modifications can alter the membrane fluidity and possibly alter the cellular transport mechanisms. Sebokova concluded in rat models that the changes in the type of oil administered to rats changed plasma membrane contents and binding capacities of the gonadotropin receptor. Other studies by Luo et al found that dietary (n-3) polyunsaturated fatty acids changed membrane potentials. Clandinin et al questioned whether diet could be used to induce formation of membrane structures that are more resistant to specific insults through the use of omega-3 fatty acids.
Differences in the rate of cancer incidence among different countries and the corresponding changes in the incidence of cancer in people who migrate from an area of lower incidence to an area of higher incidence where the diet differs, suggest that environmental factors, e.g., dietary fat, might play a role in the occurrence of this disease. Numerous epidemiological studies suggest there is an association of dietary fat with breast cancer risk and survival from breast cancer after treatment. Holm et al concluded that dietary intervention might serve as an adjuvant treatment to improve breast cancer prognosis, particularly in patients with ER-rich breast cancers. Dietary fat may have an effect on growth or spread of breast cancer, both of which may vary in accordance with the type of fat. Animal studies by Rose et al found that the type of dietary fat directly effected the extent of metastasis, being highest in mice consuming omega-6 polyunsaturated fats.